Attention-deficit hyperactivity disorder (ADHD) is a complex developmental behavioral and cognitive disorder characterized by hyperactivity, inattention and impulsivity. The most widely prescribed pharmacological treatment for ADHD patients has been psychostimulants, including methylphenidate and amphetamines. Though effective in alleviating symptoms of ADHD, these medications are commonly associated with undesirable side effects, prompting the search for novel non-psychostimulant treatments for ADHD. In addition to their potent effects on the dopamine (DA) system, psychostimulants increase the release of norepinephrine (NE) more profoundly than that of DA and serotonin (5-HT), indicating that enhancing NE neurotransmission contributes to the beneficial therapeutic effects of psychostimulants. Features of clinical ADHD are commonly modeled in juvenile rats following neonatal lesioning with 6-hydroxydopamine (6-OHDA). Such rats exhibit several characteristics resembling symptoms of ADHD including motor hyperactivity and learning deficits that can be dose-dependently antagonized by psychostimulants. A recent discovery from our laboratory is that highly selective NE transporter inhibitors (desipramine and nisoxetine) reversed the locomotor hyperactivity associated with neonatal DA lesioning in juvenile rats, suggesting that NE transporters may constitute novel targets for ADHD pharmacotherapy. This project includes further chemical, pharmacological and behavioral characterization of the role of NE transporters in the pathophysiology and treatment of ADHD. Several novel NE transporter inhibitors will be chemically synthesized using our proprietary 4-arylpiperidine pharmacophore to optimize their activity at NE transporters. This will be accomplished by modifying the 3-substitutent to exploit the rich structure-activity relationships available for increased potency and/or selectivity for NE transporters. The pharmacological profile of these compounds will be characterized by determining their affinity to NE, DA, 5-HT transporters and representative NE receptors, as well as their molecular functionality at NE transporters. The behavioral effects of novel selected compounds that exhibit high affinity and selectivity at NE transporters, and block functional reuptake of synaptosomal NE will be assessed in juvenile hyperactive rats to determine their efficacy in reversing locomotor hyperactivity. Expected findings should lead to novel compounds that can be developed as much needed innovative non-stimulant treatments for ADHD and other major neuropsychiatric disorders.